Increased T-Cell Response to Orexins in Children With Narcolepsy Type 1, Study Finds

Narcolepsy type 1 (NT1) may be caused by an autoimmune T-cell response to orexins and could be triggered by flu antigens, according to study findings published in the Annals of Clinical Translational Neurology.

The researchers enrolled 41 NTI subjects from the Sleep Disorders Clinics at Boston Children’s Hospital and Beth Israel Deaconess Medical Center. Each participant carried MHC DQB1*06:02⁺, had cataplexy, and exhibited a Multiple Sleep Latency Test demonstrating short sleep latencies and at least 2 sleep onset rapid eye movement sleep periods. The control group included 31 age and sex-matched healthy control subjects.

“NT1 is caused by a selective loss of over 90% of neurons in the lateral hypothalamus that produce orexin-A and -B (also called hypocretin-1 and -2). What causes the death of the orexin neurons remains unclear, but several lines of evidence suggest that NT1 is an autoimmune disease,” explained the study authors. “Recent reports suggest that both CD4⁺ and CD8⁺ T-cells from people with NT1 may target the orexin neuropeptides. However, whether flu cross-reactivity is a characteristic of orexin-specific T-cells remain a matter of debate.”

The study examined participants to characterize the cellular immune response to orexins mediated by CD4⁺ and CD8⁺ T-cells in peripheral blood and to determine whether it would be affected by priming these cells with flu antigen.

The study cohort included 41 participants, 27 children and 14 adults. Results revealed that the children participants with NT1 had a greater frequency of T-cells responsive to orexin than the healthy control subjects. Additionally, among children who had NT1 priming with flu peptides, significant increases in the response to orexin were shown compared to orexin restimulation alone of both the CD4⁺ and CD8⁺ T-cells.

“Unique to our findings is that we detected cytokine-producing CD4⁺ and CD8⁺ T-cells reactive to orexins in primary PBMC cultures. Furthermore, an increased frequency of these cells was found in children who, as a group, were closer to NT1 onset compared to adults, which suggests a decrease in orexin-specific T-cells circulating in blood over time,” noted the study authors. “This may explain our ability to directly identify orexin reactive T-cells ex vivo as compared to other studies in which subjects were tested longer after NT1 symptoms onset.”

The researchers suggest that future prospective studies are warranted to determine the dynamics of T-cell reactivity against orexins over time in people with NT1 that begin immediately at onset of symptoms.

Reference

Cogswell A, Maski K, Scammell T, et al. Children with Narcolepsy type 1 have increased T-cell

responses to orexins. [published online November 15, 2019]. Ann Clin Transl Neurol. doi: 10.1002/acn3.50908.